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Biomedical subjects

M E Haskins

Publications and source records attributed to M E Haskins.

At least 55 records · Page 3Linked to original sources
PubMed1989

Testicular feminization in a cat.

Testicular feminization, caused by an inherited defect of the androgen receptor, was diagnosed in a domestic cat. Individuals affected with this syndrome are genetic males that have testes but fail to undergo masculinization because the internal and external genitalia cannot respond to androgens. The affected cat had the external appearance of a sexually normal female, but during surgery for ovariohysterectomy, only 2 abdominal gonads were found. Müllerian (uterus) or wolffian (epididymides) derivatives were not present. Only testicular tissue was found in histologic sections of the gonad. A normal male chromosome constitution (38,XY) was found in karyotypes prepared from lymphocyte cultures. High affinity binding of dihydrotestosterone was undetectable in fibroblasts cultured from genital skin of the affected cat, indicating that the cytosolic androgen receptor was nonfunctional. Pedigree analysis indicates that this is an X-linked disorder in cats, as it is in other mammals. Accurate diagnosis and genetic counseling are advocated to reduce the prevalence of the disorder.

Androgen-Insensitivity Syndrome↗
PubMed1989

X-linked severe combined immunodeficiency in the dog.

This study documents the occurrence of a form of X-linked severe combined immunodeficiency (SCID) in the dog with clinical, immunologic, and pathologic features similar to those of X-linked SCID with B cells in man. The disease in the dog is characterized by growth retardation and increased susceptibility to bacterial and viral infections in young pups. Affected pups have all died or were euthanatized by 5 months with signs of canine distemper, infectious hepatitis, or bacterial pneumonia. Laboratory findings include normal numbers of circulating B lymphocytes and normal concentrations of serum IgM, but low to absent concentrations of serum IgG and IgA, indicating a defect in the terminal differentiation of IgG and IgA B cells into immunoglobulin-secreting plasma cells. This is supported by the failure of peripheral lymphocytes to produce IgG or IgA plaque-forming cells in response to polyclonal activation. There are low-to-normal numbers of circulating T cells, but a severely depressed blastogenic response to T cell mitogens. Postmortem findings include thymic dysplasia and hypoplasia of lymphoid tissue. Family studies and breeding experiments are consistent with an X-linked recessive mode of inheritance.

Animals↗
PubMed1989

Characterization of the defective beta-glucuronidase activity in canine mucopolysaccharidosis type VII.

Canine mucopolysaccharidosis type VII results from deficient activity of lysosomal beta-glucuronidase. Residual enzymatic activity (0.2-1.7% of normal) was detected in tissue homogenates from affected dogs. In contrast, serum and urine from affected animals had up to 15% residual activity. To further characterize the nature of the defective enzyme, hepatic beta-glucuronidase was partially purified from normal and MPS VII dogs for determination of their physical and kinetic properties. About 65% of the total beta-glucuronidase in normal canine liver required detergent for solubilization (i.e., membrane-associated), whereas only 22% of the residual activity in canine MPS VII liver was membrane-associated. Compared to the normal hepatic enzyme, the Km towards 4-methylumbelliferyl-beta-glucuronide was markedly increased in MPS VII dogs (i.e., 0.48 versus greater than 2.5 mmol/l). In contrast, the thermo-, cryo-, and pH stability properties, as well as the pH optimum (approximately 4.6), were essentially unaffected. In addition, the canine MPS VII hepatic residual activity was unresponsive to sulfhydryl reducing reagents and divalent cations, despite the fact that incubation of normal canine beta-glucuronidase with dithiothreitol and magnesium and/or calcium enhanced the activity more than 15-fold.

Animals↗
PubMed1989

Retinal pigment epithelial glycosaminoglycan metabolism: intracellular versus extracellular pathways. In vitro studies in normal and diseased cells.

The synthesis and turnover of glycosaminoglycans (GAGs) in different fractions of cultured feline retinal pigment epithelium (RPE) were characterized. In one method of fractionation, trypsin was used to separate the extracellular components (referred to as trypsin-soluble glycocalyx) from the intracellular components. As a second method, the basal extracellular matrix (basal ECM) was separated from the rest of the GAGs (cell-associated GAGs) by extracting the cell layer with NH4OH. The incorporation of 35SO4 into cetylpyridinium chloride-precipitable GAGs in the cell-associated and the intracellular fractions increased throughout the labeling period, while in the trypsin-soluble glycocalyx and the basal ECM incorporation approached a maximum. While heparan sulfate was the predominant GAG in all compartments, most was located extracellularly. The majority of dermatan sulfate was localized in the intracellular fraction. GAGs in the trypsin-soluble glycocalyx exhibited a rapid rate of turnover, while GAGs in the intracellular compartment and basal ECM turned over much more slowly. Ascorbic acid increased the incorporation of 35SO4 into ECM chondroitin sulfate/dermatan sulfate, but not heparan sulfate, on a per cell basis. Cycloheximide reduced incorporation of 35SO4-GAGs into both the cell-associated compartment and the basal ECM. In contrast, monensin caused a reduction in basal ECM GAGs while increasing the GAGs in the cell-associated compartment. The intracellular accumulation of GAGs and resultant pathology in alpha-L-iduronidase (alpha-L-id)-deficient RPE indicated that this pathway for the intracellular degradation of GAGs is important in normal RPE function. However, the turnover of GAGs in the trypsin-soluble glycocalyx was not affected by deficient alpha-L-id activity or by the subsequent intracellular accumulation of GAGs. Therefore, normal lysosomal activity in the RPE is not a prerequisite for maintaining the rate of extracellular GAG turnover within normal limits.

Animals↗
PubMed1988

Alterations in neuron morphology in mucopolysaccharidosis type I. A Golgi study.

Morphological changes in neurons with inborn defects of the lysosomal hydrolase, alpha-L-iduronidase, and with concomitant storage of glycosaminoglycans, were evaluated by Golgi staining in two animal models and compared to a similar study of a child with the same disease. Cortical pyramidal neurons in feline mucopolysaccharidosis type I often displayed axon hillock enlargements (meganeurites) and/or ectopic, secondary neuritic processes sprouting from this same region of the cell. The latter structures were prominent and often appeared longer than similar neurites reported in other neuronal storage diseases. Although most meganeurites were aspiny, a few were observed which possessed spine-like processes or neurites. Other than these morphological changes in cortical pyramidal neurons, few other cell types displayed abnormalities demonstrable by Golgi impregnation. In the canine model of this disorder, abnormal Golgi-impregnated cortical neurons resembled more closely those seen in human mucopolysaccharidosis. That is, they possessed meganeurites which typically were aspiny in appearance. Ectopic neurite growth was not observed on any Golgi-impregnated neurons in the cases of canine or human mucopolysaccharidosis used in this study. The latter finding, given the advanced ages of these cases, is consistent with the view that ectopic neuritogenesis seen in neuronal storage diseases may be subject to a developmental window, albeit one open well beyond the period of early postnatal maturation.

Animals↗
PubMed1986

Alpha-mannosidosis in a Persian cat.

Alpha-mannosidosis, an inherited enzyme-deficiency disease, caused growth retardation, hepatomegaly, ocular abnormalities, and neurologic dysfunction in a Persian cat. Because of the clinical progression of this autosomal recessive, lysosomal storage disorder, the cat was euthanatized at 5 months of age.

Animals↗
PubMed1986

Lethal acrodermatitis in bull terriers.

A lethal syndrome characterized clinically by growth retardation, progressive acrodermatitis, chronic pyoderma and paronychia, diarrhea, pneumonia, and abnormal behavior was observed in 17 related Bull Terrier pups. Median survival time was 7 months. Laboratory evaluation revealed non-degenerative neutrophilia, consistently low activities of serum alkaline phosphatase and alanine transaminase, and frequently, hypercholesterolemia. Lymphocyte blastogenic responses were decreased and there was dysgammaglobulinemia in pups in which quantitative studies of immunoglobulins were made. The mean of plasma zinc concentrations in 5 affected pups was significantly lower than the mean of age- and breed-matched controls. Pathologic findings included parakeratosis, hyperkeratosis, and superficial bacterial infections of the skin. There was severe reduction of lymphocytes in T-lymphocyte areas of lymphoid tissue. Bronchopneumonia and dilatation of the cerebral ventricles were found in most affected pups. Family studies indicated that the syndrome is inherited as an autosomal recessive trait. In spite of its similarities to lethal trait A46 in Black Pied Danish cattle and acrodermatitis enteropathica in man, oral or parenteral treatment with zinc failed to ameliorate the clinical signs of the syndrome.

Acrodermatitis↗
PubMed1986

Arylsulfatase B activity in cultured retinal pigment epithelium: regional studies in feline mucopolysaccharidosis VI.

Feline mucopolysaccharidosis VI (MPS VI) is a recessively inherited lysosomal storage disease resulting from a deficiency of arylsulfatase B (ASB). Previous histopathologic findings have indicated that the disease is expressed morphologically in non-pigmented retinal pigment epithelial cells (RPE) in the posterior pole and superior equatorial regions by the accumulation of vacuolated inclusions and eventual cellular hypertrophy, while pigmented regions in the periphery are minimally affected. To determine if the regional and age-dependent variations in disease severity result from differences in residual enzyme activity, primary cultures of feline MPS VI-affected RPE were initiated from defined regions of the eye and maintained in vitro for 14 days. Cultures initiated from nonpigmented areas of affected adult eyes (posterior pole, superior equatorial) were more diseased than those from pigmented (inferior-equatorial, peripheral) areas. In the nonpigmented cultures, the disease was expressed by the accumulation of single membrane-bound inclusions and cellular hypertrophy. These inclusions were indistinguishable in their morphologic appearance and distribution from those found in situ. In contrast, the cultures initiated from pigmented areas remained normal or minimally affected. The same spatial disease distribution was present in young affected eyes, but the expression of the disease was much less severe. It is apparent that temporal, spatial, and pigmentation factors were correlated with disease expression in vitro as well as in situ. Arylsulfatase B activity was measured biochemically, and found to be deficient in all regions of young and adult eyes. It was notable that there was no correlation between the level of residual enzyme activity, and the pigmentation or spatial position from which the cells were obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Inherited XX sex reversal in the cocker spaniel dog.

Nine XX true hermaphrodites and two XX males were discovered in a family of American cocker spaniels. The true hermaphrodites were partially-masculinized females with ovotestes; the XX males had malformed male external genitalia and cryptorchid aspermatogenic testes. Wolffian and Mullerian duct derivatives were present in both true hermaphrodites and XX males. All four sires of sex-reversed dogs were normal XY males; five of the dams were anatomically normal females and one was an XX true hermaphrodite. A second true hermaphrodite reproduced as a female, producing anatomically normal offspring. All matings that produced sex-reversed offspring were consanguineous. Matings of the parents of sex-reversed cocker spaniels to normal beagles with no family history of intersexuality produced only normal offspring. Examination of G-banded karyotypes of the affected animals, their parents, and siblings, revealed no structural anomalies of the chromosomes that were consistently associated with sex-reversal. In assays for serologically-detectable H-Y antigen, the group of XX true hermaphrodites and the group of XX males had mean levels of the antigen not significantly different from that in normal male controls. Female parents of sex-reversed dogs and some of their female siblings were typed H-Y antigen positive, but the mean level of the antigen in this group was less than that of normal male controls. It is proposed that XX sex reversal in cocker spaniels is due to a mutant gene which when homozygous in females, results in a level of H-Y antigen similar to that found in normal males and the gonads develop as ovotestes or testes. When the gene is heterozygous in females, the level of serologically-detectable H-Y antigen is lower than that found in normal males and the gonads develop as normal ovaries. The persistence of Mullerian structures in the presence of testicular tissue suggests that Mullerian inhibiting substance is deficient or ineffective in its action in this condition.

Animals↗
PubMed1984

Mixed lymphocyte reactivity in cats.

A method was developed to perform primary one-way mixed lymphocyte cultures (MLC) with cat cells. A polymorphic system of MLC reactivities was found within a cat population. In family studies, alloreactivity segregated as a single genetic locus with codominantly expressed products, designated feline lymphocyte defined (Fld)--although closely linked multigene control remains possible. The relationship of Fld to a putative feline major histocompatibility complex is discussed.

Animals↗
PubMed1984

Beta-glucuronidase deficiency in a dog: a model of human mucopolysaccharidosis VII.

This report describes a third mucopolysaccharidosis in animals: canine mucopolysaccharidosis VII. The affected dog was the offspring of a father-daughter mating. Weakness in the rear legs was evident at 8 weeks of age and became progressively worse. He had a large head, a shortened maxilla, and corneal granularities. Most joints were extremely lax, easily subluxated, with joint capsules that were swollen and fluctuant. The dog was alert and had apparently normal pain perception. At 13 months of age, there was radiographic evidence of extensive skeletal disease including bilateral femoral head luxation, abnormalities in the shape and density of the carpal and tarsal bones, radiolucent lesions of the epiphyseal regions of most long bones, and cervical vertebral dysplasia and platyspondylia. The electrophoretic pattern of precipitated glycosaminoglycans indicated a predominance of chondroitin sulfate. The animal died suddenly from gastric dilatation. There was generalized hepatomegaly, thickening of the atrioventricular heart valves, and generalized polyarthropathy. Vacuolated cytoplasm was observed in hepatocytes, keratocytes, fibroblasts, chondrocytes and cells of the synovial membrane, retinal pigment epithelium, and cardiac valves. Neurons had cytoplasmic vacuoles. Electron microscopy demonstrated membrane-bound cytoplasmic inclusions in polymorphonuclear leukocytes, hepatocytes, synovium, heart valves and spleen. The activities of 12 lysosomal hydrolases were determined in liver from the affected and control dogs: beta-glucuronidase (EC 3.2.1.31), beta-hexosaminidases A and B (EC 3.2.1.30), alpha-hexosaminidase (EC 3.2.1.-), alpha-L-iduronidase (EC 3.2.1.76), alpha-galactosidase A (EC 3.2.1.22), beta-galactosidase (EC 3.2.1.23), arylsulfatases A and B (EC 3.1.6.1), acid alpha-mannosidase (EC 3.2.1.24), acid beta-mannosidase (EC 3.2.1.25), and N-acetyl-D-galactosamine-6-sulfate sulfatase (EC 3.1.6.-).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Spinal cord compression and hindlimb paresis in cats with mucopolysaccharidosis VI.

Six cats with mucopolysaccharidosis VI had hindlimb paresis and other clinical signs associated with compression of the thoracolumbar spinal cord. In 5 cats, the neurologic abnormality progressed over 2 to 4 weeks to loss of thoracolumbar spinal cord function. In 1 cat, the hindlimb paresis remained stable for 18 months. In the cats with progressive worsening of hindlimb function, the abnormality was caused by compression of the spinal cord from proliferation of bony tissue in the thoracolumbar region. In all affected cats, the compression occurred from T12 to L2. In 1 cat, an attempt to relieve the clinical signs by surgery was unsuccessful.

Animals↗
PubMed1983

Tissue culture of cat retinal pigment epithelium.

To culture retinal pigment epithelial (RPE) cells from normal cats, the cells were enzymatically dissociated from the eyecup and grown in either Ham's F-10 Nutrient Mixture or Eagle's Minimum Essential Media supplemented with 20% fetal calf serum. Cultures reached confluency between 6 and 10 days and contained monolayers of polygonally shaped cells. Light and electron microscopy demonstrated that most of the normal morphological characteristics of cat RPE cells in vivo were maintained in vitro; these included apical microvilli, apicolateral junctional specializations, basal infoldings and intracellular organelles. Pigment granules appeared to be diluted by cell division. No evidence of a basal membrane formation was seen; however, a fine granular or fibrillar extracellular matrix was observed in some cultures and was located between the culture plate surface and the basal surface of the RPE. Primary cultures were viable for up to 145 days. The activities of two lysosomal hydrolases (arylsulfatase A and arylsulfatase B) involved in the metabolism of sulfatide and dermatan sulfate were measured in confluent cultures. Mean arylsulfatase A activity was 1297 nmol nitrocatechol/mg protein/hr and arylsulfatase B activity was 553 nmol nitrocatechol/mg protein/hr. These activities were approximately 5 to 10-fold higher than present in cat peripheral leukocytes and skin fibroblasts in vitro. This in vitro system will facilitate studies on normal function and in conditions where the RPE has been compromised by inherited diseases (i.e. gyrate atrophy, mucopolysaccharidosis I and VI).

Animals↗
PubMed1983

Meningiomas in young cats with mucopolysaccharidosis I.

Meningiomas are the most common central nervous system tumor of the cat, with an age at diagnosis of greater than nine years in 73% of the affected animals. Four of seven cats with alpha-L-iduronidase deficient mucopolysaccharidosis I had meningiomas at postmortem examination. All four cats were less than three years of age. The relationship between the meningiomas and the metabolic defect of MPS I is not clear.

Animals↗
PubMed1983

The pathology of the feline model of mucopolysaccharidosis I.

Five cats with feline alpha-L-iduronidase-deficient mucopolysaccharidosis were studied. Membrane-bound cytoplasmic inclusions were present in central nervous system neurons, hepatocytes, chondrocytes, vascular and splenic smooth muscle cells, bone marrow leukocytes, and fibroblasts of the skin, eye, and cardiac valves. The lesions in these cats closely resemble those described in human patients with mucopolysaccharidosis I H (Hurler syndrome).

Animals↗
PubMed1982

Purification and properties of feline and human arylsulfatase B isozymes. Evidence for feline homodimeric and human monomeric structures.

Normal feline and human arylsulfatase B isozymes were purified to homogeniety from liver. The specific activities of the feline and human enzymes toward p-nitrocatechol sulfate were 1,100,000 and 800,000 units/mg of protein, and toward UDP-N-acetylgalactosamine-4-sulfate were 5,500 and 4,000 units/mg of protein, respectively. Although both enzymes had the same pH optimum (5.7), the feline enzyme was more electronegative than the human enzyme when electrophoresed on polyacrylamide gels. Compared to the human isozyme, feline arylsulfatase B had a lower Km toward p-nitrocatechol sulfate (1.2 versus 3.6 mM), was more thermostable at 60 degrees C (68 versus 30 min), and had a slightly lower pI (7.8 versus 8.0). The native molecular weight of the feline enzyme was estimated to be about twice that the human isozyme by gel filtration, analytical polyacrylamide gel electrophoresis, and sucrose density-gradient centrifugation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed single protein bands of Mr = 41,000 and 38,000 for the feline and human isozymes, respectively. Alkylation and cross-linking experiments were consistent with the feline enzyme being a homodimer and the human enzyme a monomer. Amino acid compositional analyses revealed few significant differences between the two isozymes.

Amino Acids↗